Allogeneic hematopoietic stem cell transplantation, often referred to as bone marrow transplantation, represents a curative therapy for many individuals with leukemia, lymphoma, multiple myeloma, and myelodysplastic syndrome. However, the broadened application of transplantation therapy of these cancers is limited by two immune reactions that are mediated primarily by T cells, namely graft-versus-host disease (GVHD; T cell attack of donor cells against the patient) and graft rejection (or the host-versus-graft response; HVGR). GVHD is the main cause of lethality after transplantation. The HVGR results in the need to administer toxic doses of chemotherapy prior to transplanation, and thereby results in the current limitation of transplantation to individuals having a closely matched donor either from within the family or through the National Marrow Donor Program. Our laboratory focuses on new T cell graft engineering strategies designed to prevent GVHD and graft rejection. In murine models, we have shown that donor Th2 cells, which are generated ex vivo in the presence of the immune modulation drug rapamycin, can potently inhibit GVHD while preserving a component of the beneficial graft-versus-tumor (GVT) effect; furthermore, such Th2 cells effectively prevent the rejection of fully genetically mis-matched hematopoietic stem cells. We have made significant progress in translating these findings to the clinic. We have developed a method for generating human Th2 cells in rapamycin, and we have initiated a clinical trial investigating these cells in patients with refractory hematologic malignancy. Current data are consistent with our murine data, as recipients of Th2 cells grown in rapamycin have a low rate of acute GVHD; furthermore, administration of Th2 cells has allowed for a significant reduction in the amount of preparative chemotherapy required to achieve engraftment of the allograft. Such allogeneic Th2 cells are currently being evaluated on two clinical protocols. In the first protocol, NIH Clinical Center Protocol #04-C-0055, patients with refractory hematologic malignancy such as leukemia, lymphoma, and multiple myeloma are receiving a low-intensity transplant that is supplemented with donor Th2 cells; currently, approximately 140 patients have received therapy on this protocol. In the second protocol, NIH Clinical Center Protocol #08-C-0088, patients with refractory and metastatic renal cell carcinoma are receiving a low-intensity transplant that is supplemented with multiple infusions of donor Th2 cells. These protocols are being implemented in a multi-center manner, with Hackensack University in New Jersey serving as the multi-center site. We are also evaluating rapamycin-resistant T cells in the autologous transplantation setting. In this case, both CD4 and CD8 T cells are manufactured in the presence of IFN-alpha to skew cells towards a Th1 cytokine phenotype. We have completed a phase I clinical trial of autologous Th1-type T-Rapa cells in the context of multiple myeloma therapy (infusion of T cells after recovery from an autologous stem cell transplant procedure). Currently, we are also evaluating autologous T-Rapa cells without use of stem cell transplant for the therapy of refractory diseases. Relevant cancer sites: Non-Hodgkins Lymphoma, Multiple Myeloma. Relevant Research Areas: Bone Marrow Transplantation, Organ Transplantation Research, Hematology/Lymph, Stem Cell Research, Clinical Research.